21598290cd140623-sup-133025_1_supp_2569498_n8wssq.xlsx (43.9 kB)

Supplementary Table 4 from Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma

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posted on 2023-04-03, 20:46 authored by Eliezer M. Van Allen, Kent W. Mouw, Philip Kim, Gopa Iyer, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gregory V. Kryukov, Kevin W. O'Connor, John Sfakianos, Ilana Garcia-Grossman, Jaegil Kim, Elizabeth A. Guancial, Richard Bambury, Samira Bahl, Namrata Gupta, Deborah Farlow, Angela Qu, Sabina Signoretti, Justine A. Barletta, Victor Reuter, Jesse Boehm, Michael Lawrence, Gad Getz, Philip Kantoff, Bernard H. Bochner, Toni K. Choueiri, Dean F. Bajorin, David B. Solit, Stacey Gabriel, Alan D'Andrea, Levi A. Garraway, Jonathan E. Rosenberg

Significantly altered genes in clinical subsets. MutSigCV ranked lists for significantly mutated genes in the non-responders only (n = 25), the responders only (n = 25), and the ERCC2WT responders only (n = 16).

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ARTICLE ABSTRACT

Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q < 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma.Significance: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR.See related commentary by Turchi et al., p. 1118This article is highlighted in the In This Issue feature, p. 1103